.<BR><BR> <B>National Ovarian Cancer Prevention and Detection Study:</B> <BR><BR>The National Prospective Cohort Study of Risk-Reducing Surgery and Ovarian Screening among Women at Increased Genetic Risk of Ovarian Cancer (also known as GOG 0199) is the cornerstone of CGBs intervention studies research portfolio. Developed and chaired by Dr. Greene, it is a non-randomized natural history study of risk-reducing salpingo-oophorectomy versus a novel ovarian cancer screening strategy (the ROCA algorithm) <B>[NCI Protocol #02-C-0268]</B>. This study opened in July 2003, and closed to new patient enrollment in November 2006, after having accrued 2605 high-risk women (1029 surgery arm; 1576 screening arm). Follow-up will be completed in November 2011. This complex, multi-institution international study exemplifies the type of project that would be difficult to mount through extramural funding mechanisms. Accomplishments to date include successfully completing accrual to this study, completing the research-based BRCA1/2 mutation testing for the 1,500 mutation-unknown study participants (including both full sequencing and testing for large deletions, rearrangements), nearly completing the central pathology review of 1037 RRSO samples, publishing a report detailing the rationale and design of the study, along with baseline characteristics of the women in each cohort, developing a model of the factors which influence the choice of RRSO versus screening, contributing 1576 screening subjects to a pooled analysis (with the Cancer Genetics Network) of determinants of baseline CA-125 levels (Skates et al., unpublished data), and negotiating a collaboration between GOG and CIMBA under which DNA and clinical data from 199s 1400 mutation carriers will be contributed to pooled multiple candidate gene association studies of breast cancer risk, and two genome-wide association studies (GWAS), one for each BRCA gene.<BR><BR><B>Breast Imaging Pilot Study in Women from BRCA Mutation-Positive Families (NCI Protocol 01-C-0009):</B> <BR><BR>is the second major intervention studies programmatic component. It has reached its accrual goal of 200 women from BRCA1/2 mutation-positive families, 170 of whom are known mutation carriers. Prospective follow-up is ongoing, and scheduled to end in January 2010; 25% of subjects have completed the study. To date, breast cancer and ovarian cancer have developed in 14 and 1 participant, respectively. Analyses of baseline mammographic density and MRI volume in carriers versus non-carriers (the latter including 100 low-risk women from NCI/CCRs Breast Cancer Susceptibility Study) are well underway. These include a collaboration with Dr. Funmi Olopade and colleagues at the University of Chicago, in which our digitized mammographic images are being used to evaluate, and possibly validate, various novel imaging characteristics that may prove to be better predictors of breast cancer risk than standard mammographic density. We have published the first formal method for enumerating cells in breast duct lavage (BDL) fluid, described the results of BDL in the largest cohort of BRCA mutation carriers yet reported, and quantified the tolerability of the BDL procedure. DNA samples from mutation-positive DNA from BI participants has also been added to CGBs collection of samples being utilized in our genetic modifiers collaboration with CIMBA. Preliminary data document that fentogram quantities of estrogen metabolites are detectable in both NAF and BDL fluid, with levels in the former much higher than the latter. <BR><BR><B>A Phase II Randomized Trial of Zoledronic Acid versus Standard Care to Prevent Post-RRSO Osteopenia/Osteoporosis (GOG-215):</B> <BR><BR>was designed as a companion study to GOG-199, targeting one of the major complications of RRSO-related premature menopause, i.e., significant bone loss, increased risk of osteoporosis and fracture. Participants are enrolled in GOG-215 just prior to or immediately following RRSO; all participants receive oral calcium/vitamin D supplementation, proscription of tobacco exposure, and exercise recommendations. Half are also randomly allocated to receive 3 zoledronic acid infusions, one every 6 months. Bone mineral density and serologic markers of bone metabolism are the primary study endpoints. GOG-199 participants who cross-over from screening to surgery remain eligible for this study. The entry criteria have been relaxed to include all premenopausal women undergoing RRSO. This study is currently open at 50 sites nationwide, and has enrolled 18 participants. Dr. Larissa Korde is Co-PI of the national protocol, and also the local PI of this study which has been opened at the NIH Clinical Center <B>[NCI Protocol #06-C-0204]</B>. <BR><BR><B>A Pilot Study of a 3-month Intervention for Increasing Physical Activity in Sedentary Women at Risk of Breast Cancer:</B> <BR><BR>is also being run by Dr. Korde. She designed and initiated this project while still an oncology fellow in the Medical Oncology Branch/CCR, and has continued to run the study since joining CGB. It asks whether a physician recommendation for increasing physical activity along with the use of a pedometer will be effective in increasing physical activity in a sedentary population of breast cancer survivors and women at increased genetic risk of breast cancer <B>[NCI Protocol #04-C-0276]</B>. Changes in mammographic density, total body fat and selected hormones will be explored as surrogate biomarkers. This study has closed to accrual, and a preliminary report has been submitted for publication. <BR><BR><B>Inherited Bone Marrow Failure Syndromes:</B> <BR><BR>Our study of persons from families with one of a variety of inherited bone marrow failure syndromes (e.g., Fanconi's anemia) continues steady accrual <B>[NCI Protocol #02-C-0052]</B>. Squamous cell carcinomas of the oral cavity, esophagus, labia and cervix are among the non-hematologic malignancies which occur excessively in patients with these syndromes. Participants in this study are undergoing intensive evaluation in search of both clinical and molecular abnormalities which might represent cancer precursors, particularly with regard to cancers of the head/neck and female genitals. The role of the human papilloma virus (HPV) in the etiology of these cancers is being explored. If suitable clinical or molecular endpoints can be identified, consideration will be given to the development of an intervention program which would target persons from these high-risk families. An HPV vaccine trial among persons with FA is presently under consideration